A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease

Abstract

von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.

Conflict of interest statement

Disclosures The authors declare no competing financial interests.

Figures

Fig. 1

Temporal Change in von Willebrand factor (VWF) levels after rhIL-11 and 1-8 deamino-d-arginine vasopressin (DDAVP). The fold-increase in VWF:RCo, FVIII:C, and VWF:Ag are shown in one subject treated at dose I, the low dose level (10 μg kg−1), at baseline (white); on day 1 at 30 min (pale grey) at 4 h (dark grey); day 4 at 30 min (pale diagonal stripe) at 4 h (dark diagonal stripe); on day 7 at 30 min after rhIL-11 (before DDAVP) (vertical stripe) and 30 min after DDAVP (low density dots); and on day 14, 7 days after the last dose of rhIL-11 (high density dots). vWF:RCo, von Willebrand ristocetin cofactor; VWF:Ag, von Willebrand antigen, FVIII:C, clotting factor VIII; rhIL-11, recombinant human interleukin-11.

Fig. 2

von Willebrand factor (VWF) multimers after rhIL-11 and 1-8 deamino-d-arginine vasopressin (DDAVP). VWF multimer bands are shown from one subject treated at dose III, the high dose level (50 μg kg−1), in 1.5% agarose (top panel) and in 0.65% agarose (lower panel), with separation of low (L), medium (M), high (H), and very high (VH) multimers. The first lane is normal pooled plasma (NPP), the positive control. The second lane is plasma from a type 3 severe patient with von Willebrand disease (VWF:RCo 15 U mL−1, VWF:Ag U mL−1), the negative control. In the next lanes are screening; day 1 and day 4, pre and 30 min and 4 h post-rhIL-11; and day 7 pre-rhIL-11, post-IL-11, and 30 min and 4 h post-DDAVP. Very high-molecular-weight multimers were detected on day 7 after DDAVP treatment (indicated by arrowhead). In the last lane on day 14, very high-molecular-weight multimers returned to the baseline. vWF:RCo, von Willebrand ristocetin cofactor; VWF:Ag, von Willebrand antigen; VWF:Ag, von Willebrand antigen; rhIL-11, recombinant human interleukin-11.

Fig. 3

Platelet von Willebrand factor (VWF) mRNA expression after rhIL-11. Platelet VWF mRNA from one subject treated at dose I, the low dose level (10 μg kg−1), was isolated from platelet-rich plasma and reverse transcribed into VWF cDNA, and then amplified by quantitative PCR (see methods). When no RNA template was added, no reaction occurred and no message was detected, as seen in the yellow line. After rhIL-11, there was no change in GPIBb expression, as seen in the nearly superimposed green (baseline) and blue (after rhIL-11) lines. By contrast, after rhIL-11, there was a two- to eightfold increase in VWF mRNA expression as seen by the increase from brown (baseline) to red (after rhIL-11) lines (see arrow). NTC, no template control; rhIL-11, recombinant human interleukin-11.